Polysulfone hollow fiber semipermeable membrane

ABSTRACT

Respective hollow fiber membranes suitable for use in removing undesired contaminants from blood, in particular in an artificial kidney, have: 
     (1) per membrane area of 1.6 m 2 , in vitro clearances for urea and phosphorus respectively of ≧195, and ≧180, ml/min, a β 2  -microglobulin clearance ≧44 ml/min and an albumin permeability ≦0.5%; 
     (2) an albumin permeability ≦1.5% and an overall mass transfer coefficient Ko≧0.0012 cm/min; and 
     (3) a vitamin B 12  dialyzance of ≧135 ml/min and an albumin permeability ≦3%. The membranes can be prepared by spinning hollow fibers from a spinning solution comprising a polysulfone, a hydrophilic polymer, a solvent and water, the spinning solution having a viscosity x at 30° C. of 25-130 poise and a quantity y % of water given by: 
     
         -0.01x+1.45≦y≦-0.01x+2.25. 
    
     The membranes can be incorporated into a hemodialyzer module by a method in which they are preimpregnated with a wetting agent, thereafter kept separate from one another by spacers and then inserted in the module.

This invention relates to a hollow fiber semipermeable membrane and adialyzer, especially a hemodialyzer containing a semipermeable membraneand to methods for manufacturing the membrane and dialyzer.

As a material of the membrane used for dialyzers, there wereconventionally used a number of polymeric compounds such as celluloseacetate, polyacrylonitrile, poly(methyl methacrylate) and polyamide. Onthe other hand, polysulfone resin was initially used as an engineeringplastics material. However, on account of its distinguished features inheat stability, resistance to acids and alkalis, and bio-adaptability,it has become noted as a semipermeable membrane material. In general,most of such membranes comprised of polymeric materials are deficient inaffinity to blood because of their hydrophobic surfaces and arenot-directly usable for blood treatment. Thus, methods were devised torender them suitable for use in a dialyzer, namely by incorporating intothe membranes a hydrophilic polymer or inorganic salt as a pore formingmaterial and removing it by dissolution to form pores and, at the sametime, hydrophilically modifying the polymer surface. Among thecommercially available dialyzers currently used (three of which arereferred to hereinafter as "Company A's Membrane A", "Company B'sMembrane B" and "Company C's Membrane C") for treatment for bloodpurification, that is, blood dialysis, blood filtration and dialysis,and blood filtration, those intended to keep the albumin permeability ata low level below 0.5% did not give the effects of C_(urea) ≧195,C_(phosphorous) ≧180 and C.sub.β2-MG ≧44, ml/min, as explained morefully below. Although those of the cellulose system represented bycellulose triacetate (e.g. Company A's Membrane A), generally exhibit ahigh level of removal of low molecular weight urea, they exhibit poor β₂-microglobulin (hereinafter β₂ -MG) clearance. For Company A's MembraneA, per membrane area of 1.6 m², the in vitro urea clearance is 195ml/min or higher, the phosphorus clearance is 180 ml/min, the albuminpermeability is 0.5% or less, but the 1.8 m² conversion clearance, permembrane area of 1.8 m², of β₂ -MG is only about 23 ml/min. On the otherhand, although the polysulfone dialyzers (Company B's Membrane B, andCompany C's Membrane C) have a high capacity for removing β₂ -MG, withan in vitro clearance per membrane area of 1.8 m² of at least 44 ml/min,and an albumin permeability not more than 0.5%, the in vitro clearance,per membrane area of 1.6 m², for urea is only 192 ml/min or less and forphosphorus as low as 177 ml/min. Of the dialyzers intended to keep thealbumin permeability at a level of less than 1.5%, there is none whichhas a Ko (general mass transfer coefficient), when measured in adiffusion test with dextran having a molecular weight of 10,000, andwith measurements taken after 1 hour circulation of bovine serum, whichexceeds 0.0012 cm/min. As stated above the dialyzers of the cellulosesystem represented by cellulose triacetate (such as Company A's MembraneA) generally exhibit a high clearance of (relatively low molecularweight) urea and moreover, per membrane area of 1.6 m², the in vitroalbumin permeability is 0.5% or less. However, the Ko value, whensubjected to the abovementioned dextran diffusion test, is only about0.0002 cm/min. The polysulfone dialyzers exhibit high efficiency inremoval of β₂ -MG, but in the abovementioned dextran diffusion test, theKo value is about 0.0010 cm/min (Company B's Membrane B) or 0.0005cm/min (Company C's Membrane C). Referring now more particularly topolysulfone membranes disclosed in the patent literature, many of thesedisclosed dialyzers give an albumin permeability of less than 3.0%.However, of these dialyzers, those giving a dialyzance of vitamin B1(D_(B1)) of ≧135 ml/min or more or a dialyzance of urea (D_(urea)) of≧191 ml/min or more per 1.3 m² area in a module or a 60% or moreclearance of β₂ -microglobulin in clinical use under the blood dialysismode, are not known.

In the field of the hemodialyzers, distinguished capacities for removalof urinal toxic substances are described in JP-B-54373/1993,JP-A-23813/1994 and JP-A-300636/1992.

However, with the nowadays increasing number of long-term dialysispatients and diversification of dialysis technology, higher performancewas required of the hemodialyzers. That is, in on-line filtration anddialysis and push-pull filtration and dialysis, a very high waterpermeability is required, and in ordinary blood dialysis, a highcapacity for removal of substances of a molecular weight of 10,000 orhigher such as β₂ -microglobulin is required along with a high capacityfor removal of lower molecular weight substances Furthermore, hitherto,research was directed towards suppression, as far as practicable, of thepermeation of albumin which is a useful protein in blood. However, itwas found that harmful substances accumulating in dialysis patients werestrongly bonded to albumin, so membranes allowing permeation of acertain amount of albumin were called for, and there are a number ofreports of the improvement of symptoms by hemodialyzers using suchmembranes.

However, hemodialyzers satisfying all of these requirements have not yetbeen obtained. For example, the polysulfone membrane disclosed inJP-B-54373/1993 is good as a hemodialyzer but is not satisfactory inthat it does not provide the water permeability required inhemodialysis, hemodiafiltration and hemofiltration and removal of lowmolecular weight substances in blood dialysis. The polysulfone membranedisclosed in JP-B-300636/1992 provides a satisfactory water permeabilitybut does not have sufficient capacity for removing uremic toxins,particularly those having a high molecular weight such as β₂-microglobulin. Moreover, it involves problems in production. Forexample, during manufacture of the hemodialyzer, when incorporating theobtained hollow fiber membrane into a hemodialyzer, potting is carriedout in the presence of a wetting agent (such as glycerine) which isadded in order to maintain the water permeability. However, when usingthe membrane disclosed in JP-B-300636/1992, the hollow fibers stick toone another so that it is difficult for the potting material such aspolyurethane to permeate into the gaps of the hollow fibers, resultingin seal leakage. Thus, there is not yet provided a polysulfone hollowfiber semipermeable membrane which maintains a high blood filtrationflow and low albumin permeability over many hours in clinical use andwhich has a high urinal toxin selective permeability.

As explained above, with particular reference to commercially availabledialyzers, it has been very difficult to provide a semipermeablemembrane having high capacities for both clearance of low molecularweight urinal toxins and clearance of medium molecular weight proteinssuch as β₂ -MG, and, to our knowledge, there is no dialyzer currentlyavailable which has both of these respective capacities realizedsimultaneously. At least one aspect of the present invention addressesand solves this problem.

Similarly, no currently available membrane is capable of achieving,simultaneously a low albumin permeability, in particular ≦3, and a highmass transfer coefficient, Ko as later defined. At least one aspect ofthe invention addresses and solves this problem.

In addition, as explained above with particular reference to the patentliterature, it has also been particularly difficult to providehemodialyzers capable of achieving, on the one hand an albuminpermeability of less than 3% while at the same time achieving a D_(B1)of ≧135 ml/min and a D_(urea) of ≧191 ml/min (each per membrane area of1.3 m²) and a % β₂ -MG reduction ≧60%. At least one aspect of theinvention addresses and solves this problem.

Thus, according to a first aspect, the invention provides a hollow fibermembrane, such as a hemodialyzer, hemodiafilter or hemuofilter, having

(i) an albumin permeability of 0.5% or less;

(ii) per membrane area of 1.6 m², an in vitro urea clearance of 195ml/min or more;

(iii) per membrane area of 1.6 m², an in vitro phosphorus clearance of180 ml/min or more; and

(iv) per membrane area of 1.8 m², a β₂ -microglobulin clearance of 44ml/min or more.

According to a second aspect, the invention provides a polysulfonehollow fiber semipermeable membrane characterized by an albuminpermeability of less than 1.5% and, in a dextran diffusion test using adextran having a molecular weight of 10,000 and after 1 hour circulationof bovine serum, an overall mass transfer coefficient Ko of 0.0012cm/min or more.

Another aspect provides such a membrane according to the above first orsecond aspects of the invention for use in the treatment of blood forremoval therefrom of any undesired component, in particular use as anartificial kidney membrane, while yet another aspect provides the use ofsuch a membrane for in vitro treatment of blood.

Membranes and hollow fiber membrane artificial kidneys comprising suchmembranes provided by the above aspect of the present invention areobtainable, for example, by a method described as follows. This methoduses a stock solution obtainable by adding, to a solution having a mainhydrophobic polymer and a main hydrophilic polymer admixed and dissolvedin a solvent, an additive serving as a non-solvent or swelling agent forthe main hydrophobic polymer.

A preferred specific method of preparing the stock solution for use in amethod of the present invention will now be described in more detail.

The stock solution basically comprises a 4 component system of (1)polysulfone resin, (2) hydrophilic polymer, (3) solvent and (4)additive.

The polysulfone resin referred to here may comprise repeating units ofthe formula (1), ##STR1## and it may include, either on these or otherresidues, a functional group. Moreover, any or all of the phenylenegroups may be replaced by alkylene groups.

The hydrophilic polymer (2) is a polymer having a compatibility with thepolysulfone resin as well as a hydrophilic property. Polyvinylpyrrolidone is most desirable, but other polymers which may be presentadditionally or alternatively to the polyvinyl pyrrolidone include amodified polyvinylpyrrolidone, for example, a polyvinyl pyrrolidonecopolymer, poly(ethylene glycol) and poly(vinyl acetate). It should bechosen as appropriate for compatibility with the main polysulfonepolymer.

The solvent (3) should dissolve both the polysulfone resin (1) andhydrophilic polymer (2). As such solvents, a variety of solvents may beused, including dimethyl sulfoxide, dimethyl acetamide, dimethylformamide, N-methyl-2-pyrrolidone and dioxane, but dimethyl acetamide,dimethyl sulfoxide, dimethyl formamide and N-methyl-2-pyrrolidone areparticularly preferable.

For the additive (4), any material can be used so long as it iscompatible with the solvent (3) and serves as a good solvent for thehydrophilic polymer (2) and a non-solvent or swelling agent for thepolysulfone resin (1), and, in particular such a material may be water,methanol, ethanol, isopropanol, hexanol or 1,4-butanediol. However,considering the cost of production, water is most preferable. Theadditive (4) should be chosen with the coagulation of the polysulfoneresin (1) taken into consideration.

Howsoever and which of these components are combined is optional, and itwill be a matter of ease for those skilled in the art to select aparticular combination giving the desired coagulation property.Furthermore, either or both of the solvent (3) and additive (4)respectively may be a mixture of two or more compounds.

In the case of a stock solution containing a polysulfone resin,hydrophilic polymer and solvent such as that for use in a methodembodying the present invention, the additive (4) is to be carefullychosen for the poly-sulfonic resin (1). In particular, it should be freefrom mutual interaction with the polysulfone resin (1), such that thepolysulfone resin (1) maintains a homogenous system on account of theadditive (4) to such a concentration at which it coagulates as a matterof course and has no phase separation produced in a system having nohydrophilic polymer (2) admixed. Here, if the temperature is raised, themolecular motion increases to weaken the bond particularly between thehydrophilic polymer (2) and the additive (4), then the hydrogen bond isbroken, and so the apparent concentration of the additive (4) which isnot bonded to the polysulfone resin (1) increases over that at theinitial temperature T, resulting in mutual interaction between thepolysulfone resin (1) and the additive (4) with consequent coagulationand phase separation of the polysulfone resin (1). When the quantity ofthe additive (4) in this system is increased, the stock solution systemat the temperature T has the additive (4) added in an amount in excessof the amount held by the hydrophilic polymer (2) at the temperature T,and so the membrane forming stock solution undergoes a phase separation.However, when the temperature is lowered, molecular motion of thehydrophilic polymer (2) is reduced to increase the amount of bonding ofthe additive (4) and thus decrease the apparent concentration of theadditive (4), and so the system becomes homogeneous again. If thetemperature is raised again, the system becomes inhomogeneous, but withthe hydrophilic polymer (2) added, the amount of the additive (4)bonding with the hydrophilic polymer (2) increase to give a homogeneoussystem.

A preferred range of concentrations of the polysulfone resin (1) whichcan allow formation of a membrane having the characteristics desired fora hollow fiber membrane dialyzer of the present invention is 13-20% byweight of the solution. To obtain a high water permeability and a largefractional molecular weight, the polymer concentration should besomewhat reduced, and it is more preferably 13-18% by weight. If it isless than 13% by weight, a sufficient viscosity of the membrane formingstock is difficult to obtain, making it difficult to form a membrane. Ifit exceeds 20% by weight, hardly any penetrating pores are formed.

The hydrophilic polymer (2) or, more specifically, polyvinylpyrrolidoneis commercially available in molecular weights of 360,000, 160,000,40,000 and 10,000, and such a polymer is conveniently used, although apolymer of any other molecular weight can of course be used. Thehydrophilic polymer (2) suitable for the hollow fiber membrane dialyzeris preferably added, particularly in the case of polyvinylpyrrolidone,in an amount of 1-20% by weight or, more preferably, 3-10% by weight,but the amount added is governed by the molecular weight of thepolyvinylpyrrolidone. When the amount added is too small, hardly anyphase separation occurs, and when the polymer concentration is high andthe polymer molecular weight is too large, washing after formation ofthe membrane becomes difficult. Thus, one of the methods for obtaining asatisfactory membrane is to use polymers of different molecular weightand have them mixed to assume the roles desired of them.

In order to prepare the solution, the polymers (1) and (2) may beadmixed, the mixture dissolved in the solvent (3), then the additive (4)added. In the case of water in particular, it is highly coagulative forthe polysulfone polymer of the formula (1), so it should be strictlycontrolled, preferably to an amount of 1.8 percent by weight or less or,more preferably, 1.05-1.70% by weight. in the case of polyacrylonitrile,it is especially preferable to add this in an amount of 2-6% by weight.When a less coagulative additive (4) is used, the amount added increasesas a matter of course. Adjustment of the added amount of such acoagulative additive has a relationship with the equilibrium moisturecontent of the hydrophobic polymer. As the concentration of the additive(4) increases, the phase separation concentration of the membraneforming stock solution decreases. The phase separation temperatureshould be determined in consideration of the pore radius of the desiredmembrane. Typically the membrane is formed by a wet or dry/wet spinningprocess, preferably a dry/wet spinning process in which the solutionpasses through a dry zone containing a gas, typically air, at apredetermined relative humidity and thereafter through a coagulatingbath containing a coagulating agent. In such a process, in the dry zonea preferred relative humidity is 60-90%, a preferred temperature is25-55° C., more preferably 30-50° C. and a preferred residence time is0.1-1 sec, while in the coagulating bath a preferred temperature is25-55° C., more preferably 30-50° C. The form of the hollow fibermembrane used in the dialyzer of the invention may be provided byallowing an infusing solution to flow inside the stock solution when itis discharged from the annular spinning orifice and run through a dryingzone to a coagulation bath. Here, the humidity of the dry zone is veryimportant. By supplying moisture through the outer surface of themembrane while running it through the wet section, this enablesacceleration of the phase separation at about the outer surface andenlargement of the pore diameter, thus providing the effect of reducingthe permeation and diffusion resistance at the time of dialysis. If therelative humidity is too high, coagulation of the stock solution on theouter surface prevails to reduce the pore diameter, resulting in anincrease in the permeation and diffusion resistance at the time ofdialysis. Such relative humidity is governed greatly by the compositionof the stock solution, so it is difficult to define simply the optimumpoint, but a relative humidity of 60-90% is preferably used. For ease ofprocessing, the infusing solution preferably comprises basically thesolvent (3) used in the stock solution. The composition of the infusingsolution directly affects the permeation and diffusion capacities of theactivated layer, so it must be precisely determined. In the foregoingrange of stock solution compositions, the composition of the infusingsolution is greatly affected by the composition of the stock solution,so it is difficult to define simply the optimum point. Here, whendimethylacetamide, is used, for example, an aqueous solution of 60˜75%by weight is preferably used.

It is very difficult to define the optimum membrane forming stocksolution, but through combination of the properties of the fourcomponents within the above range of compositions, a particular stocksolution can be chosen for providing a desired polysulfone hollow fibersemipermeable membrane of the invention.

Particular reference has been made earlier to problems arising from themethods of preparing hemodialyzers disclosed, for example,JP-B-54373/1993, JP-A-23813/1994 and JP-A-300636/1992, especially thedifficulty in achieving an albumin permeability of ≦3% while at the sametime achieving, a D_(B1) of at least 135 ml/min and a D_(urea) of atleast 191 ml/min, each per membrane area of 1.3 m² and % β₂ -MGreduction ≧60%, all measured under conditions as later described.

According to at least a third aspect of the invention, membranesproviding such a simultaneous combination of characteristics can beobtained.

Thus, the invention provides, according to yet another aspect, apolysulfone hollow fiber membrane having an albumin permeability ≦3% anda D_(B1) (per membrane area of 1.3 m²) of ≧135, preferably a ≧140ml/min, and preferably also a D_(urea) (per membrane are of 1.3 m²)≧191,more preferably ≧193 ml/min, and also preferably a %β₂ -MG reduction≧60%, more preferably ≧70%.

In particular, by using hollow fibers obtainable by spinning aparticular spinning solution (which may be as described above inrelation to aspects of the invention earlier described) and infusingsolution under particular conditions of the drying zone (details ofwhich are described later), a membrane having characteristicsparticularly desirable for hemodialysis can be obtained, and, moreover,a hemodialysis module containing such membranes can be provided withoutdeterioration of the membrane, thereby maintaining such desiredcharacteristics. For such a purpose, the module is fabricated with asufficient amount of a wetting agent imparted to the hollow fibers, andafter the wetting agent has been removed, the hollow fibers can befilled with water to give a desired product. Here, if the bundle ofhollow fibers is provided with the wetting agent imparted to the hollowfibers, the hollow fibers stick to one another to make it difficult toform a sealing plate by the potting material, according to one aspect ofthe invention, so in a more preferable method, spacers are inserted toprevent adhesion.

That is, according to one aspect of the invention, a polysulfone hollowfiber type hemodialyzer is manufactured by a method characterized bypreparing a bundle of hollow fibers with a sufficient amount of awetting agent imparted to the hollow fibers, forming them into at leastone sealing plate, preferably a pair of sealing plates, one at eachrespective opposite axial end region of the hollow tubular fibers, thenrinsing the wetting agent with water and sterilizing, which hemodialyzeris thereby capable of exhibiting an albumin permeability of 3.0% or lessand a vitamin B₁₂ dialyzance, per membrane area of 1.3 m², of 135 ml/minor higher.

Furthermore, according to this manufacturing method, by employingpreferable conditions described herein, it is possible to obtain ahemodialyzer which is characterized by an albumin permeability of 0.1%to 2.4% and a vitamin 12 dialyzance of 137 ml/min or higher. Moreover,through as combination of more preferable conditions, it is possible toobtain a hemodialyzer which is characterized by an albumin permeabilityof 0.3% to 2.0% and a vitamin B₁₂ dialyzance of 140 ml/min or higher.

Also, by employing more and more preferable manufacturing conditions inthe manufacturing method of the present invention, it is possible toobtain a hemodialyzer exhibiting a urea dialyzance of 191 ml/min orhigher, 192 ml/min or higher, and even 193 ml/min or higher.

Furthermore, according to the method of the present invention, again byemploying more and more preferable conditions, a hemodialyzer having ahollow fiber membrane exhibiting a water permeability as high as 500ml/hr.mmHg.m² or higher, 600 ml/hr.mmHg.m² or even 700 ml/hr.mmHg. m² orhigher is obtainable. Indeed, a hollow fiber membrane obtained by amethod of the present invention and giving the best clinical evaluationexhibited a water permeability higher than 800 ml/hr.mmHg.m².

The % removal of β₂ -microglobulin and the dialyzance of vitamin B₁₂ inclinical evaluation are positively correlated, and the vitamin B₁₂dialyzance may be regarded as the best index of the membrane capacity.

Preferred conditions and process steps in methods embodying theinvention are now described.

The concentration of the polysulfone resin in the spinning solution inthe manufacturing method according to the invention is preferably 14-22%by weight and more preferably 17-19% by weight.

The concentration of the hydrophilic polymer is preferably 5-12% byweight and more preferably 7-10% by weight.

For obtaining a hollow fiber membrane of good characteristicsparticularly as a hemodialyzer by spinning at a high speed (which isdesirable for reasons of economy), the viscosity of the spinningsolution is an important factor. Too low a viscosity is not preferred inthat end breakage or variation of hollow fiber diameter occurs whilecontrol of the albumin permeability becomes difficult. On the otherhand, too high a viscosity is not preferred in that variation of thethickness of the hollow fiber membrane is enlarged while its capacity toclear urinal toxic substances is reduced.

In the spinning solution according to the manufacturing method of theinvention, especially if dimethylacetamide is used as a solvent, theviscosity at 30° C. is preferably within the range of 25-130 poise(about 35-170 poise at 20° C.) or, more preferably, 40-110 poise.

Control of the viscosity may be made through adjustment of theconcentration and/or molecular weight of the polysulfone resin and/orconcentration and/or molecular weight of the hydrophilic polymer in thespinning solution. The most preferable method is to change the molecularweight of the hydrophilic polymer.

For example, a desired Viscosity may be provided by mixingpolyvinylpyrrolidone (K-30) of a weight average molecular weight ofabout 40,000 and polyvinylpyrrolidone (K-90) of a weight averagemolecular weight of about 1,100,000 and changing the mixing ratio.

In a preferred specific example, where dimethylacetamide is used as asolvent, AMOCO Corporations's Polysulfon P-3500 used in a concentrationof 18% by weight, and polyvinylpyrrolidone used in a concentration of 9%by weight, the mixing ratio of K-30 and K-90 is within the range ofabout 9/0-5/4 or, more preferably, about 8/1-5.5/3.5.

In the spinning solution used in a method according to the presentinvention, it is preferable to add a small amount of water as an agentto regulate the pore diameter in the hollow fiber membrane.

Thus, according to a particular method aspect of the invention there isprovided a method of manufacturing a polysulfone hollow fiber membrane,which method comprises spinning hollow fibers from a spinning solutioncomprising a polysulfone, a hydrophilic polymer, a solvent for each ofthe polysulfone and hydrophilic polymer and water, which spinningsolution has a viscosity x (poise) at 30° C. within the range of 25-130poise and a quantity y (wt %) of water present in the spinning solutionwithin the range satisfying the formula

    -0.01x+1.45≦y≦-0.01x+2.25.

When such a method is employed and more particularly, when the mostpreferred solvent, dimethylacetamide is used, a hollow fiber membrane ofgood characteristics is obtainable. When the water quantity y (wt %)contained in the solution is within the range satisfying the formula

    -0.01+1.65≦y≦0.01x+2.05,

it is more preferable. In the above formulae, x represents the viscosity(poise) at 30° C. of the spinning solution, and x is within the range of25-130 poise or preferably 40-110 poise.

When the amount of water added is smaller, clouding of the spinningsolution due to long storage may be checked (here, it seems that theclouding occurs as the polysulfone oligomer crystallizes, and this isnot desirable in that if the clouding proceeds, end breakage tends tooccur in spinning), but the pore diameter is reduced to reduce thecapacity of the membrane for clearing substances of a molecular weightof 10,000 or higher such as β₂ -microglobulin, and this is notdesirable. Conversely, when the amount of water added is greater, thisis not desirable in that the spinning solution tends to lose stabilityand cause clouding, and furthermore the albumin permeability becomes toohigh.

Moreover, in a preferred manufacturing method of the invention, aninfusing solution is extruded from the center of the spinneret tocontrol the inner surface of the hollow fiber by its coagulation andthus provide a membrane having good characteristics as a hemodialyzer.The infusing solution is generally used for the purpose of graduallycoagulating the spinning solution from the inner surface of the hollowfiber to form an asymmetric structure, preferably having an overallporosity of at least 78% and preferably having a fine active layer ofthe separation membrane, which preferably has an average pore radius ≦10nm, more preferably ≦8 nm, especially ≦7 nm. Hence the infusion fluid ispreferably low in its ability to cause coagulation, and an organicsolvent such as alcohol is usable independently or in a mixture withwater.

According to the present invention, a mixture of the solvent used forthe spinning solution and water is preferable for ease of recovery andfor obtaining high performance, and a mixed solvent ofdimethylacetamide, which is the most preferable solvent, and water ismore preferable.

When a mixture solvent of dimethylacetamide and water is used, thequantity of water z (weight %) contained in the infusing solution isdefined by the viscosity of the spinning solution in order to obtain amembrane having good characteristics as a hemodialyzer of the invention,and it is preferably in the range satisfying the formula

    0.14x+25.5≦z≦0.14x+37.5

and it is more preferable that the water quantity z (weight %) containedin the infusing solution is in the range satisfying the formula

    0.14x+28.5≦z≦0.14x+34.5

where x is the viscosity (poise) of the spinning solution at 30° C. andx is within the range of 25-130 poise or more preferably 40-110 poise.

A membrane having good characteristics as a hollow fiber membrane forhemodialysis is obtainable by having both water quantity y (weight %) inspinning solution and water quantity z (weight %) in infusing solutionto satisfy the foregoing formulae respectively.

If the water content is less, coagulation of the spinning solution orthat from the inner surface is slow, tending to cause end breakage inthe drying zone and higher permeation of proteins including albumin.Likewise, an excessive water quantity is not preferable in that thecapacity of the membrane to remove substances of greater molecularweight such as β₂ -microglobulin is reduced. On the other hand, itscapacity to remove low molecular substances is also reduced as the watercontent is increased further.

The hollow fiber membrane of the present invention may be spun by thewet spinning method according to which the spinning solution andinfusing solution provided as stated above are directly led from theannular nozzle spinneret to the coagulation bath or by the dry/wetspinning method according to which the hollow fiber from the spinneretis once exposed to a gaseous phase then led to the coagulation bath.Here, in order to obtain good performance, the dry/wet spinning methodhaving the fiber run in the gaseous phase (drying zone) preferably for0.1-1.0 second or, more preferably, 0.2-0.8 second is desirable.

As the condition of the drying zone, a relative humidity of 40% or moreis preferred, and a good performance is provided through contact with amoist air flow of a relative humidity of preferably at least 60%, evenmore preferably 70% or higher, most preferably 80% or higher, say up to90%.

Next, the spinning solution, now in the form of hollow fiber spun out ofthe spinneret is led to the coagulation bath. In the coagulation bath,it comingles with the solvent, but as it comes into contact with thecoagulating solution which is a non-solvent having a property tocoagulate the polysulfone resin, it forms a membrane of a structure inthe form of a coarse porous sponge as a supporting layer from the sideof the outer surface.

For the coagulation bath, a non-solvent or a mixture of two or morenon-solvents may be used, but from the point of view of recovery of thesolvent, a mixture of the solvent of the spinning solution and water ispreferably used.

The hollow fiber coming out of the coagulation bath is rinsed with waterfor removal of a substantial part of the solvent component, and it isimmersed in a solution of a wetting agent, cut to a predetermined lengthand assembled to provide a predetermined number of fibers. Then, thesolution of the wetting agent, which has substituted the infusingsolution inside the hollow fiber at the time of immersion, is removed toform a bundle of hollow fibers.

For the wetting agent, there may be used an alcohol such as glycerine,ethylene glycol, polypropylene glycol or polyethylene glycol whichprevents drying of the bundle of hollow fibers even when it is allowedto stand in air or an aqueous solution of an inorganic salt; however,glycerine is particularly preferable.

It is especially preferred to use an aqueous solution of glycerine,preferably containing 50% or more by weight, more preferably 60-75% byweight, still more preferably 65-72% by weight of glycerine in order toprevent deterioration of the permeability of the membrane throughdrying.

Imparting the wetting agent may prevent deterioration of the membraneperformance while fabricating it into a hemodialyzer. However,conversely, in forming a sealing plate by means of a potting materialsuch as a polyurethane, a problem arises in that adhesion of the hollowfibers to one another tends to occur and this renders it very difficultfor the potting material to permeate into the gaps of the hollow fibers,resulting in seal leakage precluding separation of blood and dialyzateby the sealing plate. In order to resolve such a problem, a method whichmay be employed is that of storing the bundle of hollow fibers in anatmosphere of low humidity for a long period of time after it has beeninserted into a casing of the hemodialyzer (for example, storing in aroom of a relative humidity of 40% for about 3 days) or that ofloosening the ends of the fiber bundle by applying an air flow of a verylow humidity to end parts, then a strong air flow in a verticaldirection to both end faces, of the hollow fiber bundle (for example,applying air at a temperature of 40-50° C. and a relative humidity of10% or less to both end parts of the casing for about 2 hours, thenblowing air strongly in a vertical direction upon the end parts toloosen the hollowfibers at the end parts) before formation of thesealing plate. However, the more preferable method is to introducespacers for preventing adhesion of the hollow fibers to one anotherduring the process before preparation of the hollow fiber bundle afterthe wetting agent has been added.

When used as a hemodialyzer, this method of introducing the spacers hasalso another effect of allowing the dialyzate to flow to the centralpart of the hollow fiber bundle to enhance the dialytic performance.Introduction of the spacers may be implemented by imparting spacer yarnsof polyester, polyamide, polyacrylonitrile, cellulose acetate, silk orcotton along, or helically winding them around, one or two hollowfibers.

To completely prevent the seal leakage by such a method, it may benecessary to use a thick spacer yarn of a diameter of about one half ormore (about 120 microns or more) of the outer diameter of hollow fiber,leading to a greater diameter of the case of the hemodialyzer, and thisis not so preferable. A more preferable method is to introduce spacersin two steps, as described below. That is, in the first step, unithollow fiber elements are produced by the method of either imparting orhelically winding spacer yarns of polyester or the like along or aroundone or two hollow fibers and, in the second step, bundles of hollowfibers are provided by helically winding the spacer yarns as spacersaround an aggregate of four or more said unit hollow fiber elements, andfive or more of said hollow fiber bundles are assembled into a bundle ofa specified number of hollow fibers for a hemodialyzer. In this case,the unit hollow fiber elements are preferably provided by the helicalwinding method.

For the spacer yarns introduced in the first and second steps,relatively bulky and stretchable crimped fibers, finished yarns and spunyarns are preferably used. In addition, their thickness is preferablyfiner than that of the polysulfone hollow fiber, more preferably about1/20 of the outer diameter of hollow fiber, and a fineness of 1/2 to1/10 of the outer diameter of hollow fiber is preferable.

Such introduction of spacers facilitates formation of the sealing plateunder conditions where the wetting agent is imparted in a concentration(quantity) sufficient to prevent deterioration of the performance of themembrane by drying, and by this procedure, hemodialyzers having a highwater permeability and a high capacity for removal of urinal toxicsubstances and having an albumin permeability controlled to 3% or less,are obtainable in a high yield.

Fabrication (modulation) of the bundles of hollow fibers thus obtainedinto hemodialyzers is practicable by any conventional method.

That is, for example, fiber bundles are inserted in a case of, say,polystyrene resin, and using a potting material such as a polyurethane,a sealing plate through which the hollow fibers pass is formed at eachend of the case using a centrifugal force, then a leak test is performedbefore the bundles are formed into the hemodialyzer.

Next, the very small amount of solvent and wetting agent which mayremain in the hollow fiber membrane is removed by washing with water,then sterilization is carried out while water fills the membrane toprovide a desired hemodialyzer product. Washing may be carried out usingwater at about room temperature, up to, say, 90° C., but is preferablycarried out at a temperature of at least 40° C. In particular, it takesa period of about 2 hours at 55° C. or 15 minutes at 80° C., so washingwith warm water at 55° C. or higher is especially preferable. It is alsopossible to employ repeated washing, for example, washing for a shorttime, then warming at 50° C. or higher, and again washing for a shorttime.

In the case of a blend membrane additionally containing a water-solublehydrophilic polymer, there is a danger of dissolution of the hydrophilicpolymer when used for medical purposes.

Here, it is possible to cross-link the hydrophilic polymer and thus makeit insoluble by radiation and/or heat. Specifically, a heat treatment(about 120° C.) may be given, or gamma-rays or electron beams may beirradiated under wet conditions. The exposure dose is adequately 15-35KGy under a submerged condition. When a dose exceeding 20 KGy isirradiated, it is possible to carry out a sterilizing treatmentsimultaneously. Radiation of gamma-rays or electron beams producescovalent bonds with the polymer materials, and the dissolution of thehydrophilic polymer is checked. In the case of the heat treatment, thehydrophilic polymer itself gels into a higher molecule and insolubleform. For sterilization, any conventional method is applicable, that is,sterilization with hot water of at 90° C. or higher or sterilization byradiation using gamma-rays or electron beams under the water filledcondition. Sterilization by radiation using gamma-rays or electron beamsis a preferable method in that it renders the hydrophilic polymer in themembrane insoluble through cross-linking. When usingpolyvinylpyrrolidone which is the most preferable hydrophilic polymerpresent in a membrane according to the invention, radiation ofgamma-rays in a dosage within the range of about 20 KGy-35 KGy causesinsolubility through cross-linking of the polyvinylpyrrolidone alongwith sterilization as required for medical equipment, and hence this isthe most practical method of sterilization.

Radiation sterilization gives rise to insolubility through cross-linkingof polyvinylpyrrolidone simultaneously and thus checks the dissolutionof the polymer and enhances the safety of the product. In addition, bythis method, it is possible to allow much more polyvinylpyrrolidone tobe present in the hollow fibers of the product to provide a membranehaving good affinity with water and thus exhibit the high performanceattainable by membranes embodying the present invention. Forinsolubility through cross-linking of polyvinylpyrrolidone, it is ofcourse possible to separately apply radiation before sterilization, butit is preferable for obtaining a membrane of high performance tosimultaneously implement the cross-linking and sterilization byradiation.

Preferred embodiments of the invention will now be described in moredetail with reference to the following Examples in which parts are byweight unless otherwise stated.

Evaluation of the performance of membranes according to the inventionwas made by the following methods.

(1) Water Permeability

Using 30 hollow fibers of a length of about 15 cm obtained by cuttingthe case of a completed hemodialyzer product i.e. subsequent to itsradiation by gamma-rays, a small glass tube module is prepared byrepotting respective opposite ends of the fibers, and the differentialpressure between the inside and outside of the membrane, that is,intermembrane differential pressure, is measured by permeation of waterat a pressure of about 100 mmHg and expressed in ml/hr.mmHg.m². Thewater permeation performance was calculated by the following formula.

    UFR(ml/hr/m.sup.2 /mmHg)=Qw/(P×T×A)

where Qw is the amount of the filtrate (ml), T the efflux time (hr), Pthe pressure (mmHg), and A the area of the membrane (m²) (in terms ofthe area of the inner surface of the hollow yarn).

(2) Determination of Diffusion by Dextran

Basically, this measurement is made similarly to that of the dialyticcapacity. It is generally as follows. Firstly, a hollow fiber membranedialyzer has a blood side thereof perfused with 500 ml of warmed bovineserum at 37° C. at 200 ml/min for 50 minutes but without any flow of thedialysate, then the dialysate is removed and filtration, controlled bythe flow rate of the perfusate, occurs at a rate of 20 ml/min for 10minutes (the foregoing process being regarded as 1-hour circulation ofbovine serum). After storing for 12 hours in a refrigerator, thedialyzer is washed by priming with two liters of physiological saltsolution before it is used for testing. Dextrans of respective varyingmolecular weights (FULKA's product, weight-average molecular weights of400, 1000, 2000, 20000, 50000 and 200000) are each dissolved in waterfor ultrafiltration at respective concentrations each of 0.5 mg/ml so asto provide a solution containing 3 mg/ml of dextran with a distributiontherein of molecular weights. This solution is warmed up to 37° C., andfed to the blood side (inside of the hollow fibers) by a blood pump at aflow rate of 200 ml/min, while the dialyzate side has ultrafiltratedwater kept at 37° C. and fed at 500 ml/min in countercurrent flow tothat of the blood. Here, the filtering pressure should be adjusted tozero. Accordingly, the diffusing capacity of the membrane is determinedunder conditions under which no ultrafiltration is caused. Feeding iscontinued for 20 minutes until an equilibrium state is established, thensamples are taken at the inlet and outlet of the blood side and thedialyzing side. Sample solutions are subjected to analysis by a GPCcolumn (TOSO GPXL3000) at a column temperature of 40° C., and thetransfer phase at 1 ml/min of pure water for liquid chromatography andsample drive of 50 μl. The general mass transfer coefficient is thenobtained by determining the change of concentration at the inlet andoutlet of the blood side. Thereafter, the Ko value at a pointcorresponding to a dextran molecular weight of 10,000 is obtained. Here,calibration must be made with dextran of a definite molecular-weightdistribution used before the sample is applied to the GPC column. Thegeneral mass transfer coefficient is calculated using the followingformula:

    Clearance, Ct(ml/min)= (CBi-CBo)/CBi!Q.sub.B               ( 2)

where CBi: module inlet side concentration; CBo: module outlet sideconcentration; and QB: module supply liquid (perfusate) flow rate(ml/min).

General mass transfer coefficient Ko(cm/min)

    =Q.sub.B / A×10.sup.4 ×(1-Q.sub.B /Q.sub.D)×1n  1-(C.sub.L /Q.sub.D)!/ 1-(C.sub.L /Q.sub.B)!!            (3)

where

A=area (m²); and

Q_(D) =dialysate flow rate (ml/min).

(3) Measurement of Albumin Permeability

Bovine blood (heparin treated blood), of hematocrit value 30% and totalprotein 6.5 g/dl, in fed to the inside of the hollow fiber at 200ml/min. Controlling the outlet pressure, the filtration is adjusted to arate of 20 ml/min, and the filtrate is returned to the blood tank. Onehour after starting of refluxing, the blood and filtrate at the inletand outlet of the hollow fiber side are sampled. Analyzing the bloodside by BCG method and filtrate side by CBB method kits, the albuminpermeability (%) is calculated from the concentrations: ##EQU1## whereCf: albumin content in filtrate; CBi: albumin content at module inlet;and CBo: albumin content at the module outlet.

(4) Determination of in vitro β₂ -MG Removal Capacity

Basically, this determination is made similarly to that of the dialyticcapacity. In a minimodule of a membrane area of 25 cm², human β₂ -MG isdissolved in a concentration of 5 mg/ml in 30 ml of prefiltered bovineserum, and the solution is perfused to the inside of the hollow fibersat a rate of 1 ml/min, while to the outside of the hollow fibers, 140 mlof phosphate buffered saline (PBS) kept at 37° C. is perfused at a rateof 20 ml/min in a closed system. After 4-hours perfusion, the solutionsof perfusion on the inside and outside of the hollow fibers arecollected. Then, the clearance is calculated, and its value per membranearea of 1.8 m² is obtained.

(5) Determination of the Clearances of Urea and Phosphorus

Preparing 501 of a physiological salt solution containing each of 1000ppm of urea and 50 ppm of phosphoric acid as blood (i.e. perfusate)solution and 1001 of physiological salt solution as dialysis solution,the concentrations at the blood side inlet and outlet of the dialyzerare measured with the blood flow set at 200 ml/min, dialyzate flow at500 ml/min, and the standard clearances on the blood and dialyzate sidesare calculated, and their mean values are used.

(6) Determination of Porosity

A sample is observed using a scanning electron microscope to confirmthat substantial macrovoids (referring to a structure in whichmacrovoids open discontinuously) in the inner layer part and theporosity is calculated from the fiber weight G in a dry condition,hollow fiber membrane size (inner diameter ID and membrane thicknessWT), polymer specific gravity d and hollow fiber length 1 as follows:##EQU2## (7) Observation of Membrane Structure

Freeze drying the hollow fiber membrane, the structures of itscross-section and inner surface are observed by a scanning electronmicroscope. The average pore radius of the active layer is calculatedthrough measurement of a freeze dried sample (3.5 cm length, 0.2 g) bythe N2 adsorption method (BET method).

(8) (%) β₂ -Microglobulin Removal

Blood dialysis is carried out upon six patients of a weight of 50 kg-60kg and a β₂ -microglobulin level of 25-35 mg/l, heparin being added tothe blood during dialysis as an anti-coagulant, with a blood flow at 200ml/min, dialyzate flow at 500 ml/min, and water removal in 4 hours at2.5-3.51, and the β₂ -microglobulin concentrations before and after thedialysis are measured and calculated by the latex immuno-agglutinationmethod, with compensation made for the protein concentration, and themean value is used. The % globulin removal is calculated from ##EQU3##where:

C_(tp1) is the total protein concentration before dialysis;

C_(tp2) is the total protein concentration after dialysis;

C.sub.β2-MG1 is the total β₂ -M_(G) concentration before dialysis; and

C.sub.β2-MG1 is the total β₂ -MG concentration after dialysis.

(9) Viscosity of Spinning Solution

30 Measurement is made using a B-type viscosimeter (TOKIMEKKU Corp.,DV-B11 digital viscosimeter) and the spinning solution sampled in anamount of 300 ml or more, with care taken so that the measurement wouldnot be affected by the inner diameter of the vessel.

(10) Dialyzances of Urea and Vitamin B₁₂

A perfusate for dialysis is obtained by dissolving each of 60 g of ureaand 1.2 g of vitamin B₁₂ in 60 liters of water, concentrations ofperfusate at the perfusate inlet and outlet and concentrations ofdialyzate at the dialyzate inlet and outlet of the dialyzer are measuredwith the perfusate flow set at 200 ml/min, dialyzate flow at 500 ml/min,and filtration speed at 10 ml/min, then the blood-based anddialyzate-based dialyzances are calculated, and their mean valuesexpressed in ml/min are employed.

EXAMPLE 1

18 Parts of a polysulfone (AMOCO's Udel-P3500) and 9 parts ofpolyvinylpyrrolidone (BASF K30) were added to 71.95 parts ofdimethylacetamide and 1.05 parts of water, and the mixture was heated at90° C. for 12 hours to dissolve the components into a spinning solution.This solution was extruded from an annular spinning orifice of outerdiameter 0.3 mm and inner diameter 0.2 mm together with a solutionconsisting of 65 parts of dimethylacetamide and 35 parts of water as acore solution within a sheath of the spinning solution. The core/sheathpassed from the orifice into a dry zone which is 300 mm in length andwhich contains air at a relative humidity of 88% and a temperature of30° C., at a speed of 40 m/min. The core/sheath then entered acoagulating bath of a 20% aqueous dimethylacetamide solution at atemperature of 40° C., in which a hollow fiber membrane was formed. Thishollow fiber membrane was inserted in a case to form a module with amembrane area of 1.6 m² with potting. After irradiation of the modulewith gamma-rays with the membrane in a wet condition, clearances of ureaand of phosphorus and albumin permeability were determined. The in vitrourea clearance was found to be 196 ml/min, phosphorus clearance was 181ml/min, and albumin permeability was 0.12%. Further, the 1.8 m²conversion clearance, i.e. clearance per area of 1.8 m², of β₂ -MG was44 ml/min.

EXAMPLE 2

18 Parts of a polysulfone (AMOCO's Udel-P3500) and 9 parts ofpolyvinylpyrrolidone (BASF K30) were added to 71.70 parts ofdimethylacetamide and 1.30 parts of water, and the mixture was heated at90° C. for 12 hours to dissolve the components into a membrane stocksolution. This solution was extruded from an annular spinning orifice ofouter diameter 0.3 mm and inner diameter 0.2 m together with a solutionconsisting of 65 parts of dimethylacetamide and 35 parts of water as acore solution to form a hollow fiber membrane under the same conditionsas in Example 1, except that the relative humidity of the air in the dryzone was 73% and the dry zone length was 350 mm. This hollow fibermembrane was inserted in a case to form a module with a membrane area of1.6 m² through potting. After gamma-ray irradiation with the membrane ina wet state, clearances of urea and of phosphorus and albuminpermeability were determined. The in vitro urea clearance was 196ml/min, phosphorus clearance was 188 ml/min, and albumin permeabilitywas 0.17%. The 1.8 m² conversion clearance of β₂ -MG was 53 ml/min.

EXAMPLE 3

18 Parts of a polysulfone (AMOCO's Udel-P3500) and 12 parts ofpolyvinylpyrrolidone (BASF K30) were added to 68.55 parts ofdimethylacetamide and 1.45 parts of water, and the mixture was heated at90° C. for 12 hours to dissolve the components into a membrane stocksolution. This solution was extruded from an annular spinning orifice ofouter diameter 0.3 mm and inner diameter 0.2 mm together with a solutionconsisting of 65 parts of dimethylacetamide and 32 parts of water as acore solution to form a hollow fiber membrane under the same conditionsas in Example 1, except that the relative humidity of the air in the dryzone was 85% and the dry zone length was 350 mm. This hollow fibermembrane was inserted in a case to give a module with a membrane area of1.6 m² through potting. After gamma-ray irradiation with the membrane ina wet state, clearances of urea and of phosphorus and albuminpermeability were determined. The in vitro urea clearance was 197ml/min, phosphorus clearance was 185 ml/min, and albumin permeabilitywas as 0.32%. The 1.8 m² conversion clearance of β₂ -MG was 59 ml/min.

Comparative Example 1

18 Parts of a polysulfone (AMOCO's Udel-P3500) and 9 parts ofpolyvinylpyrrolidons (BASF K30) were added to 72.00 parts ofdimethylacetamide and 1.0 part of water, and the mixture was heated at90° C. for 12 hours to dissolve the components and thus give a membranestock solution. This solution was extruded from an annular spinningorifice of outer diameter 0.3 mm and inner diameter 0.2 mm together witha solution consisting of 65 parts of dimethylacetamide and 35 parts ofwater as a core solution to form a hollow fiber membrane under the sameconditions as in Example 1, except that the relative humidity of the airin the dry zone was 85% and the dry zone length was 350 mm. This hollowfiber membrane was inserted in a case to give a module with a membranearea of 1.6 m² through potting. After gamma-ray irradiation with themodule in a wet state, the clearances of urea and of phosphorus andalbumin permeability were determined. The urea clearance was 195 ml/min,phosphorus clearance was 181 ml/min, and albumin permeability was 0.12%.The 1.8 m² conversion clearance of β₂ -MG was 42 ml/min.

EXAMPLE 4

18 Parts of a polysulfone (AMOCO's Udel-P3500) and 9 parts ofpolyvinylpyrrolidone (BASF K30) were added to 71.7 parts ofdimethylacetamide and 1.3 parts of water, and the mixture was heated at90° C. for 12 hours to dissolve the components into a membrane stocksolution. This solution was extruded from an annular orifice provided byrespective axial ends of a pair of coaxial tubes of outer diameter 0.3mm and inner diameter 0.2 mm together with a solution consisting of 70parts of dimethylacetamide and 30 parts of water as a core solution toform a hollow fiber membrane under the same conditions as in Example 1,except that the relative humidity of the air in the dry zone was 85%,the length of the dry zone was 250 mm and the coagulation temperaturewas 50° C. This hollow fiber membrane was inserted in a case to form amodule with a membrane area of 1.6 m² through potting. Next, aftergamma-ray radiation in a wet state, the albumin permeability wasdetermined, and it was 0.75%, and in the diffusion test with dextran,the general mass transfer coefficient Ko after 1 hour circulation ofbovine serum was, at the dextran molecular weight 10,000, 0.0018 cm/min.

This hollow fiber membrane was confirmed to be a membrane having aspongy structure in the internal layer part, a hydrophilic propertyprovided by polyvinylpyrrolidone, a porosity of 79.5% and anasymmetrical structure with an average pore radius of active layer of6.7 nm.

EXAMPLE 5

19 Parts of a polysulfone (AMOCO's Udel-P3500) and 9 parts ofpolyvinylpyrrolidone (BASF K30) were added to 70.7 parts ofdimethylacetamide and 1.3 parts of water, and the mixture was heated at90° C. for 12 hours to dissolve the components and form a membrane stocksolution. This solution was extruded from an annular orifice (providedas in Example 4) of outer diameter 0.3 mm and inner diameter 0.2 mmtogether with a solution consisting of 70 parts of dimethylacetamide and30 parts of water as a core solution to form a hollow fiber membraneunder the same conditions as in Example 1, except that the relativehumidity of the air in the dry zone was 85%, the dry zone length was 250mm and the coagulation temperature was 50° C. This hollow fiber membranewas inserted in a case to give a module with a membrane area of 1.6 m²through potting. Next, after gamma-ray irradiation with the membrane ina wet state, the albumin permeability was measured, and was 0.58%, andin a dextran diffusion test, the general mass transfer coefficient Koafter 1 hour circulation of bovine serum was, for a dextran molecularweight of 10,000, 0.0015 cm/min.

This hollow fiber membrane was confirmed to be a membrane having aspongy structure in the inner layer part, and to have a hydrophilicproperty provided by the polyvinylpyrrolidone, a porosity of 78.2% andan asymmetrical structure with an active layer having an average poreradius of 6.2 nm.

EXAMPLE 6

19 Parts of a polysulfone (AMOCO's Udel-P3500) and 9 parts ofpolyvinylpyrrolidone (BASF K60) were added to 70.0 parts ofdimethylacetamide and 2.0 parts of water, and the mixture was heated at90° C. for 12 hours to dissolve the components into a membrane stocksolution. This solution was extruded from an annular orifice (providedas in Example 4) of outer diameter 0.3 mm and inner diameter 0.2 mmtogether with a solution consisting of 63 parts of dimethylacetamide and37 parts of water as a core solution to form a hollow fiber membraneunder the same conditions as in Example 1, except that the dry zonelength was 350 mm and the coagulation temperature was 50° C. This hollowfiber membrane was inserted in a case to form a module with a membranearea of 1.6 m² through potting. Next after gamma-ray irradiation withthe membrane in a wet state, the albumin permeability was measured, andwas 1.38%, and in a dextran diffusion test, the general mass transfercoefficient Ko after 1 hour circulation of bovine serum was, for adextran molecular weight of 10,000, 0.0022 cm/min.

This hollow fiber membrane was confirmed to be a membrane having aspongy structure in the internal layer part, a hydrophilic propertyprovided by polyvinylpyrrolidone, a porosity of 81.2% and anasymmetrical structure with an active layer having an average poreradius of 6.8 nm.

Comparative Example 2

18 Parts of a polysulfone (AMOCO's Udel-P3500) and 9 parts ofpolyvinylpyrrolidone (BASF K30) were added to 71.95 parts ofdimethylacetamide and 1.05 parts of water, and the mixture was heated at90° C. for 12 hours to dissolve the components into a membrane stocksolution. This solution was extruded from an annular orifice (providedas in Example 4) of outer diameter 0.3 mm and inner diameter 0.2 mmtogether with a solution consisting of 65 parts of dimethylacetamide and35 parts of water as a core solution to form a hollow fiber membraneunder the same conditions as in Example 1. This hollow fiber membranewas inserted in a case to form a module with a membrane area of 1.6 m²through potting. Then, after gamma-ray irradiation with the membrane ina wet state, the albumin permeability was measured and was 0.12%, and ina dextran diffusion test, the general mass transfer coefficient Ko was,after 1 hour circulation of bovine serum, 0.0009 cm/min.

This hollow fiber membrane was confirmed to be a membrane having aspongy structure in the inner layer part, a hydrophilic propertyprovided by the polyvinylpyrrolidone, a porosity of 78.2% and anasymmetrical structure with active layer having an average pore radiusof 5.3 nm.

EXAMPLE 7

18 Parts of a polysulfone (AMOCO's "P-3500"), 6 parts ofpolyvinylpyrrolidone (BASF's "K30"; molecular weight, about 40,000) and3 parts of polyvinylpyrrolidone (BASF's "K90"; molecular weight, about1,100,000) were added to a mixed solution of 71.95 parts ofdimethylacetamide and 1.05 parts of water, and the mixture heated at 80°C. with stirring for 12 hours to dissolve the components, to prepare aspinning solution. This spinning solution was a homogeneous, slightlyopaque but otherwise clear solution of a viscosity of 76.9 poise at 30°C.

This spinning solution was extruded from an annular nozzle spinneret at30° C., while an infusing solution prepared by mixing 60 parts ofdimethylacetamide and 40 parts of water was introduced from a centralpart of the spinneret nozzle. Setting the length of the dry zone at 250mm and allowing moist air of a relative. humidity of 88% to flow in thesection, spinning was carried out at a speed of 40 m/min. The hollowthread was then led to a coagulation bath (dimethylacetamide/water(weight ratio)=20/80) at a temperature of 40° C., and the hollow threadcoming out of the coagulation bath was washed and then immersed in a 68%by weight aqueous solution of glycerine. After removing the excessiveglycerine sticking to the surface, a unit hollow fiber element wasprovided by helically winding a finished false twist polyester yarn of50 denier 5 filaments (about 88 microns) around 2 hollow fibers in a Zdirection at 0.5 winding per 10 mm of hollow fiber. Then, assembling 24units of such unit hollow fiber elements, the same finished polyesteryarn was wound around the assembly nearly at the same pitch in an Sdirection. By thus providing 2 layers of spacers, an assembly of unithollow fiber elements was fabricated. By assembly then of 221 assembliesof unit hollow fiber elements, a hollow fiber bundle was provided. Thishollow fiber bundle was revolved in a centrifugal separator to removethe aqueous solution of glycerine replacing the infusing solution andsealed in the hollow threads to give a bundle of hollow fibers to beinserted in a hemodialyzer case. This hollow fiber had an inner diameterof 200 microns and an outer diameter of 280 microns, and the hollowfiber bundle had 10,608 hollow fibers assembled in it.

This hollow fiber bundle was inserted in a hemodialysis case of an innerdiameter of 40 mm. Then, with a temporary cap fitted to each end of thecase, polyurethane was introduced from the inlet of the dialysissolution and then solidified. Removing the temporary caps and cuttingoff the polyurethane and the end parts of hollow thread bundle comingout of the ends of the case, header caps were fitted, and a leak testwas conducted using air at a pressure of 0.8 kg/cm².

As the result of the leak test using 1000 samples, failures were foundin 12 samples. Looking into the cause, they were found to be caused byend breakage and thread cut due to simple failure in work or contact ofthe hollow fiber bundle with the end part or inner wall of the case whenit was inserted in the case, and there was no seal leakage found in thepolyurethane sealing plate.

Next, a module found acceptable in the leak test was washed with purewater running through a reverse osmotic membrane for 30 minutes at 80°C. and packed. Then, it was irradiated and sterilized by gamma-rays at apower of 32 KGy, and a hemodialyzer of an effective length of 195 mm andan effective area of 1.3 m² was provided. This dialyzer was found to beacceptable for all items of the approval standard for hemodialysisapparatus. The water permeability of the hollow fiber cut out of thismodule was 815 ml/hr.mmHg.m². The albumin permeability of the module was1.2%, urea dialyzance was 195 ml/min, and vitamin B₁₂ dialyzance was 143ml/min.

In addition, when this module was used for clinical evaluation, it gavea very high % β₂ -microglobulin removal at 73% and was found usablewithout any problem such as residual blood.

EXAMPLE 8

18 Parts of a polysulfone (AMOCO's "P-3500") and 9 parts ofpolyvinylpyrrolidone (BASF's "K-30") were added to a mixed solution of71.6 parts of dimethylacetamide and 1.40 parts of water, and the mixturewas heated at 90° C. with agitation for 12 hours to dissolve thecomponents and form a spinning solution. This spinning solution had aviscosity of 28.4 poise at 30° C. (38.8 poise at 20° C).

This spinning solution was extruded from an annular nozzle spinneret at30° C., while an infusing solution prepared by mixing 65 parts ofdimethylacetamide and 35 parts of water was injected from the centralpart of the spinneret. The solution emitted from the spinneret entered adry zone set at a length of 350 mm, where it was exposed to moist air ofa relative humidity of 84% in this section. Spinning was carried out ata speed of 40 m/min, and a hemodialyzer was fabricated by a methodsimilar to that in Example 7. However, during the course of fabrication,a leak test was conducted with 1000 samples used. Failures occurred in17 samples, but the causes were the same with those in Example 7.

The thus obtained dialyzer of an effective area of 1.3 m² was foundacceptable for all items of the approval standard of hemodialyzers. Thewater permeability of the hollow fiber cut out of the dialyzer was 10ml/hr.mmHg.m², and the albumin permeability of the module was 0.4%, andthe urea and vitamin B₁₂ dialyzances were respectively 194 ml/min and139 ml/min. In the clinical evaluation of this module, it gave a % β₂-microglobulin removal of 67% and was found usable without any problemsuch as residual blood.

EXAMPLE 9

18 Parts of a polysulfone (AMOCO's "P-3500") and 9 parts of apolyvinylpyrrolidone (BASF's "K-30") were added to a mixed solution of71.8 parts of dimethylacetamide and 1.2 parts of water, and the mixturewas heated at 80° C. with agitation for 12 hours to dissolve thecomponents and form a spinning solution. This solution had a viscosityof 26.8 poise at 30° C. Then, using as an infusing solution, acomposition of 60 parts of dimethylacetamide and 40 parts of water, ahemodialyzer was prepared by a method similar to that in Example 7.

The water permeability of the hollow fiber cut out of this dialyzer was740 ml/hr.mmHg.m², the albumin permeability of the module was 0.1%, andthe urea and vitamin B₁₂ dialyzances were respectively 192 ml/min and136 ml/min, per area of 1.3 m². When this module was used for a clinicaltest, it gave a % β₂ -microglobulin removal of 62% and was found usablewithout any problem such as residual blood.

EXAMPLE 10

Assembling 170 and 306 bundles of hollow fibers in the course of processof Example 7, bundles of hollow fibers were prepared, and they wereinserted in hemodialysis eases of inner diameter 35.5 mm and 46.5 mmrespectively to produce hemodialyzers by the same method as that inExample 7.

The effective areas were respectively 1.0 m² and 1.8 m², and when thevitamin B₁₂ dialyzances were measured, they were 127 ml/min and 165ml/min.

EXAMPLE 11

Using the bundle of hollow fibers in the course of process of Example 9but changing the assembled number of fibers, bundles of hollow fiberswere prepared. Then, they were inserted in hemodialysis cases of innerdiameters of 35.5 mm, 44.0 mm and 46.5 mm, and hemodialyzers witheffective areas of 1.0 m², 1.6 m² and 1.8 m² were prepared by the samemethod as that in Example 9.

Measuring the urea and vitamin B12 dialyzances and albuminpermeabilities, the urea dialyzances were 187 m/min, 195 ml/min and 197ml/min; vitamin B₁₂ dialyzance were 122 ml/min, 147 ml/min and 156ml/min; and albumin permeabilities were 0.2%, 0.1% and 0.2%,respectively.

Comparative Example 3

18 Parts of a polysulfone (AMOCO's "P-3500") and 9 parts of apolyvinylpyrrolidone (BASF's "K-30") were added to a mixed solution of44 parts of dimethylacetamide, 28 parts of dimethylsulfoxide and 1.0part of water, and the mixture was heated at 80° C. with agitation for15 hours to dissolve the components and form a spinning solution. Thisspinning solution had a viscosity of 32.9 poise at 30° C. This spinningsolution was extruded from an annular orifice nozzle spinneret at 30°C., while, as an infusing solution, an admixture of 60 parts ofdimethylacetamide and 40 parts of water was injected through the centralpart of the spinneret. Then, a hemodialyzer was prepared by the samemethod as that in Example 7.

The water permeability of the hollow fiber cut out of the dialyzer was830 ml/hr.mmHg.m², the albumin permeability of the module was 0.2% andthe vitamin B₁₂ dialyzance was 132 ml/min. In a clinical test to whichthis module was subjected, the β₂ -microglobulin removal rate was as lowas 49%.

Comparative Example 4

After washing the coagulated and desolvated hollow thread of Example 7,it was immersed in a 45% by weight aqueous solution of glycerine. Afterthe excessive glycerine sticking to the surface was removed, it wastaken on a hexagonal hank, each side of which had a length of 60 cm, andair dried at room temperature. Then, by cutting it out of the hank, abundle of hollow fibers was prepared. This hollow fiber bundle was anassembly of 10,608 hollow fibers. The hollow fiber bundle was insertedin a hemodialysis case of an inner diameter of 40 mm, and dry air wasblown vertically to both end faces of the hollow fiber bundle to loosenthe end parts. Then, sealing plates were formed by the same method asthat in Example 7. Introducing pressure air from the dialyzate side andfilling water to the blood side, a leak test was made according to thebubble point method. Then, through the gamma-ray sterilization by thesame method as that in Example 7, a hemodialyzer was prepared.

The water permeability of the hollow fiber cut out of this module was410 ml/hr.mmHg.m², albumin permeability was 0.3%, urea dialyzance was190 ml/min, and vitamin B₁₂ dialyzance was 125 ml/min. These values ofwater permeability and urea and vitamin B₁₂ dialyzance were allrelatively low. That is, when a low concentration of glycerine is added,the tube plate may be formed readily without spacers, but deteriorationin the permeability of the hollow fiber occurred due to drying. Thus itwas difficult to produce a hemodialyzer of high performance such as thataccording to the present invention.

We claim:
 1. A hollow fiber membrane characterized by,(i) an albuminpermeability no more than 0.5%; (ii) per membrane area of 1.6 m², an invitro urea clearance of at least 195 ml/min; (iii) per membrane area of1.6 m², an in vitro phosphorus clearance of at least 180 ml/min; (iv)per membrane area of 1.8 m², a β₂ -microglobulin clearance of at least44 ml/min.
 2. A hollow fiber membrane according to claim 1, whichcomprises a polysulfone resin.
 3. A hollow fiber membrane according toclaim 2, which comprises a polysulfone and a hydrophilic polymer.
 4. Ahollow fiber membrane according to claim 3, wherein the hydrophilicpolymer comprises polyvinylpyrrolidone.
 5. A hollow fiber membraneaccording to claim 3, wherein the hydrophilic polymer is cross-linked.6. In a method, for the treatment of blood to remove therefrom undesiredmaterial, in which blood is separated from dialysate by a hollow fibermembrane capable of allowing selective passage across said membrane theimprovement comprising using a hollow fiber membrane characterized by(i)an albumin permeability no more than 0.5%; (ii) per membrane area of 1.6m², an in vitro urea clearance of at least 195 ml/min; (iii) permembrane area of 1.6 m², an in vitro phosphorus clearance of at least180 ml/min; (iv) per membrane area of 1.8 m², a β₂ -microglobulinclearance of at least 44 ml/min.
 7. A polysulfone hollow fibersemipermeable membrane characterized by an albumin permeability of lessthan 1.5% and, in a dextran diffusion test using a dextran having amolecular weight of 10,000 and after 1 hour circulation of bovine serum,and overall mass transfer coefficient Ko of at least 0.0012 cm/min, andhaving a β-microglobulin clearance of at least 44 ml/min, per membranearea of 1.8 m2.
 8. A polysulfone hollow fiber membrane according toclaim 7, wherein the membrane has a hydrophilic property provided by ahydrophilic polymer, a porosity of at least 78% and an asymmetricalstructure including an active layer thereof, which active layer has anaverage pore radius of less than 10 nm.
 9. In a method for treatment ofblood to remove therefrom undesired material, in which blood isseparated from dialysate by a hollow fiber membrane capable of allowingselective passage across said membrane characterized by an albuminpermeability of less than 1.5% and, in a dextran diffusion test using adestran having a molecular weight of 10,000 and after 1 hour circulationof bovine serum, and overal mass transfer coefficient Ko of at least0.0012 cm/min, and having a β-microglobulin clearance of at least 44ml/min, per membrane area of 1.8 m2.
 10. A polysulfone hollow fibermembrane containing a hydrophilic polymer in the membrane characterizedby an albumin permeability of no more than 3.0% and a vitamin B₁₂dialyzance of at least 135 ml/min per membrane area of 1.3 m², thevitamin B₁₂ dialyzance being measured during dialysis using, asperfusate, an aqueous solution containing urea and vitamin B₁₂ at aperfusate flow rate of 200 ml/min, and using, as a dialyate, water at adialysate flow rate of 500 ml/min and a filtration speed of 10 ml/min.11. A polysulfone hollow fiber membrane according to claim 10, having analbumin permeability of 0.1% to 2.4% and a vitamin B₁₂ dialyzance of atleast 137 ml/min per membrane area of 1.3 m².
 12. A polyoulfone hollowfiber membrane according to claim 11 having an albumin permeability of0.3% to 2.0% and a vitamin B₁₂ dialyzance of at least 140 ml/min in amodule per membrane area of 1.3 m².
 13. A polysulfone hollow fibermembrane according to claim 10, wherein the urea dialyzance per membranearea of 1.3 m² is at least 191 ml/min, the urea dialyzance beingmeasured during dialysis of blood containing added urea and vitamin B₁₂at a blood flow rate of 200 ml/min, using water as a dialysate at adialysate flow rate of 500 ml/min and a filtration speed of 10 mi/min.14. A polysulfone hollow fiber membrane according to claim 13, whereinthe urea dialyzance per membrane area of 1.3 m² is at least 192 ml/min.15. A polysulfone hollow fiber membrane according to claim 14, whereinthe urea dialyzance in a module of a membrane area of 1.3 m² is at least193 ml/min.
 16. A polysulfone hollow fiber membrane according to claim10, wherein the water permeability of the hollow fiber is at least 500ml/hr.mmHg.m².
 17. A polysulfone hollow fiber membrane according toclaim 15, wherein the water permeability of the hollow fiber is at least600 ml/hr.mmHg.m².
 18. A polysulfone hollow fiber membrane according toclaim 17, wherein the water permeability of the hollow fiber is at least700 ml/hr.mmHg.m².
 19. A polysulfone hollow fiber membrane according toclaim 17, wherein the said % β₂ -microglobulin removal is at least 70%.20. A polysulfone hollow fiber membrane according to claim 10, having a% β₂ -microglobulin removal, in clinical use for blood dialysis with amodule per membrane area of 1.3 m², of at least 60%.
 21. A polysulfonehollow fiber membrane according to claim 10, wherein the hydrophilicpolymer is polyvinylpyrrolidone.
 22. In a method, for the treatment ofblood to remove therefrom undesired material, in which blood isseparated from dialysate by a hollow fiber membrane capable of allowingselective passage across said membrane the improvement comprising usinga hollow fiber membrane containing in the membrane a hydrophilic polymerand characterized by an albumin permeability of no more than 3.0% and avitamin B₁₂ dialyzance of at least 135 ml/min per membrane area of 1.3m², the vitamin B₁₂ dialyzance being measured during dialysis of bloodcontaining added urea and vitamin B₁₂ at a blood flow rate of 200ml/min, using water as a dialysate at a dialysate flow rate of 500ml/min and a filtration speed of 10 ml/min.